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Int. J. Mol. Sci. 2015, 16(8), 18293-18311;

Potential Effects of Phytoestrogen Genistein in Modulating Acute Methotrexate Chemotherapy-Induced Osteoclastogenesis and Bone Damage in Rats

Sansom Institute for Health Research, School of Pharmacy and Medical Science, University of South Australia, Adelaide, SA 5001, Australia
Department of Physiology, School of Medical Sciences, University of Adelaide, Adelaide, SA 5001, Australia
Department of Orthopaedic Surgery, Women's and Children's Hospital, North Adelaide, SA 5006, Australia
Institute of Orthopaedics, Lanzhou General Hospital, Lanzhou Command of Chinese People's Liberation Army, Lanzhou 730050, China
Nutritional Physiology Research Centre, School of Health Sciences, University of South Australia, Adelaide, SA 5001, Australia
Clinical Nutrition Research Centre, University of Newcastle, Callaghan, NSW 2308, Australia
Author to whom correspondence should be addressed.
Academic Editors: Paula Andrade and Patrícia Valentão
Received: 8 July 2015 / Accepted: 3 August 2015 / Published: 6 August 2015
(This article belongs to the Special Issue Phenolics and Polyphenolics 2015)
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Chemotherapy-induced bone damage is a frequent side effect which causes diminished bone mineral density and fracture in childhood cancer sufferers and survivors. The intensified use of anti-metabolite methotrexate (MTX) and other cytotoxic drugs has led to the need for a mechanistic understanding of chemotherapy-induced bone loss and for the development of protective treatments. Using a young rat MTX-induced bone loss model, we investigated potential bone protective effects of phytoestrogen genistein. Oral gavages of genistein (20 mg/kg) were administered daily, for seven days before, five days during, and three days after five once-daily injections (sc) of MTX (0.75 mg/kg). MTX treatment reduced body weight gain and tibial metaphyseal trabecular bone volume (p < 0.001), increased osteoclast density on the trabecular bone surface (p < 0.05), and increased the bone marrow adipocyte number in lower metaphyseal bone (p < 0.001). Genistein supplementation preserved body weight gain (p < 0.05) and inhibited ex vivo osteoclast formation of bone marrow cells from MTX-treated rats (p < 0.001). However, MTX-induced changes in bone volume, trabecular architecture, metaphyseal mRNA expression of pro-osteoclastogenic cytokines, and marrow adiposity were not significantly affected by the co-administration of genistein. This study suggests that genistein may suppress MTX-induced osteoclastogenesis; however, further studies are required to examine its potential in protecting against MTX chemotherapy-induced bone damage. View Full-Text
Keywords: methotrexate; chemotherapy; osteoporosis; genistein methotrexate; chemotherapy; osteoporosis; genistein

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King, T.J.; Shandala, T.; Lee, A.M.; Foster, B.K.; Chen, K.-M.; Howe, P.R.; Xian, C.J. Potential Effects of Phytoestrogen Genistein in Modulating Acute Methotrexate Chemotherapy-Induced Osteoclastogenesis and Bone Damage in Rats. Int. J. Mol. Sci. 2015, 16, 18293-18311.

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